Understanding the role of lifetime ovulatory years and DNA repair variants on ovarian cancer risk in the United Kingdom Biobank

Background: Epithelial ovarian cancer (EOC) risk factors span protective exposures such as parity and contraceptive use, and risk-elevating traits including early menarche and late menopause. Together, these factors dictate lifetime ovulatory years (LOY), which may drive carcinogenesis via an ovulation-induced, DNA-damage promoting microenvironment. Methods: This study tested the theory that DNA repair capacity and LOY are synergistic partners by evaluating gene-environment interaction between DNA repair capacity (the presence of pathogenic variants in DNA repair genes in 251,476 at-risk females in the United Kingdom (UK) Biobank, including 847 incident EOC cases) and LOY, using a novel DNA repair capacity score. Results: We confirmed the association between increasing LOYs and EOC risk in the UK Biobank (hazard ratio [HR]: 1.15 [1.10, 1.20] per 5-year increase in LOY). We also observed strong associations between pathogenic DNA repair variants and ovarian cancer; individuals with at least one variant in 163 DNA repair genes evaluated had a significantly increased hazard of EOC (HR: 1.27, 95% CI: 1.05, 1.55). Participants with both high LOY and at least one variant had an HR of 2.00 (1.54, 2.59), however we did not observe gene-LOY interaction. Conclusions: We detected evidence that increasing LOYs and pathogenic DNA repair variants are independent risk factors of EOC, with no evidence of synergy in this population. Impact: In the UK Biobank, greater lifetime ovulations were associated with ovarian cancer risk. Rare pathogenic DNA repair variants also conferred high risk, independent of ovulatory years.